Lei Zuo

Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family

AIMS Hypertrophic cardiomyopathy (HCM) mainly results from autosomal-dominant inherited single heterozygous mutations in cardiac sarcomere genes. Contributions of multiple gene mutations to disease heterogeneity in a three-generation family were investigated. METHODS Clinical, electrocardiographic (ECG), and echocardiographic examination in members of a three-generation Chinese family was followed by exon and boarding intron analysis of 96 genes in the proband using second-generation sequencing. The identified mutations were confirmed by bi-directional Sanger sequencing in all family members and 300 healthy controls. RESULTS Four missense mutations were detected in the family. These were two novel MYH7-H1717Q and MYLK2-K324E mutations accompanied by the KCNQ1-R190W and TMEM70-I147T mutations. The proband carried all four mutations and showed overlapping HCM and LQT1 phenotypes. Five family members each carried two mutations. Subject II-2 only carried TMEM70-I147T. MYH7-H1717Q and TMEM70-I147T came from the paternal side, whereas KCNQ1-R190W and MYLK2-K324E came from the maternal side. Left ventricle mass indices in MYH7-H1717Q carriers were significantly higher than in non-H1717Q carriers (90.05 ± 7.33 g/m(2), 63.20 ± 4.53 g/m(2), respectively, P < 0.01). Four KCNQ1-R190W carriers showed QTc intervals that were significantly more prolonged than those in non-R190W carriers (472.25 ± 16.18 and 408.50 ± 7.66 ms, respectively, P < 0.05). All MYLK2-K324E carriers showed inverted ECG T waves. The subject with only a TMEM70-I147T mutation showed normal ECG and echocardiographs, suggesting that this had less pathological effects at least in this family. CONCLUSIONS We demonstrate dual LQT1 and HCM phenotypes in this multiple LQT1- and HCM-related gene mutation carrier family for the first time and suggest that LQT-related gene mutations associate with QT interval prolongation and/or arrhythmia in HCM patients.

Reduction of left ventricular longitudinal global and segmental systolic functions in patients with hypertrophic cardiomyopathy: Study of two-dimensional tissue motion annular displacement

The early detection of abnormal left ventricular systolic functions in patients with hypertrophic cardiomyopathy (HCM) remains a challenge. The aim of this study was to identify a novel method for the assessment of left ventricular systolic function in patients with HCM. A total of 65 patients with HCM were included in this study. The patients were divided into obstructive HCM (HOCM; 16 cases) and non-obstructive HCM (NOHCM; 49 cases) groups. The healthy control group comprised 48 participants. Two-dimensional (2D) speckle-tracking technology was used to measure the left ventricular global and segmental longitudinal strains and mitral annular displacement (MADs). Compared with healthy control group, the six segmental strains and the global strain of the left ventricle (LSglobal) increased while six segmental MADs and MADglobal of the mitral annulus decreased in the HOCM and NOHCM groups (P<0.05). In addition, the six segmental MADs of the mitral annulus were significantly negatively correlated with the six segmental strains of the left ventricle (r=−0.744 to −0.647, P<0.001). MADglobal was significantly negatively correlated with LSglobal (r=−0.857, P<0.001). The tissue motion annular displacement (TMAD) at the midpoint was significantly negatively correlated with LSglobal (r=−0.871, P<0.001). The 2D TMAD technique of measuring MAD was feasible and practically approachable for rapidly evaluating the left ventricular longitudinal global and segmental systolic functions of patients with HCM.

Stable H3 peptide was delivered by gold nanorods to inhibit LSD1 activation and induce human mesenchymal stem cells differentiation

Recently, lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, regulates post-translational modifications and has great promise as new targets for cancer and other diseases. Moreover, the ability of LSD1 to induce the differentiation of stem cells has attracted great attention in biological fields. In this study, we designed LSD1 peptide inhibitor based on its substrate H3 peptide. Through introducing a disulfide bond to stabilize the native peptide into alpha helical structure, we get a peptide with higher cell permeability and stability compared to its parent form. Using gold nanorods (AuNRs) as delivery systems to deliver stable peptide into human MSCs, the delivery efficiency has been enhanced significantly by flow cytometry and cell fluorescent imaging. The intracellular delivery of stable peptide by AuNRs-PEI-based nanocarriers could inhibit the activation of LSD1, which together with hepatocyte growth factor (HGF) exhibits obviously synergistic effect to induce human MSCs differentiation. Furthermore, the hepatic marker genes AFP (alpha fetal protein) and ck19 are up-regulated by AuNRs-stable peptide (AuNRs- SP- PEI) with HGF. In conclusion, our study is the first time to use stable H3 peptide to inhibit LSD1 activation, which has been further delivered by AuNRs as nanocarriers into human MSCs.

The Cumulative Effects of the MYH7 -V878A and CACNA1C -A1594V Mutations in a Chinese Family with Hypertrophic Cardiomyopathy

Aims: We investigated the pathogenesis of MYH7-V878A and CACNA1C-A1594V mutations in a Chinese family with hypertrophic cardiomyopathy. Methods: Clinical, electrocardiographic (ECG), echocardiographic, and cardiac magnetic resonance (CMR) examinations of members of a Chinese family were followed by exon and boarding intron analyses of 96 genes in the proband using second-generation sequencing. We confirmed the mutations by bidirectional Sanger sequencing in the members and in 300 healthy controls. Results: We detected MYH7-V878A and CACNA1C-A1594V mutations in this family. The members with both mutations showed inverted T-waves and ST-segment depression in ECG recordings, severe left ventricular (LV) hypertrophy in echocardiography, and myocardial fibrosis in CMR; subject II-11 did not show late gadolinium enhancement. Among those with only the MYH7-V878A mutation, subject III-7 showed abnormal ECG recordings, asymmetric septal hypertrophy, and myocardial fibrosis, and subjects II-13 and III-15 showed some abnormal repolarization, borderline LV wall thickness, and normal CMR findings. Those with only the CACNA1C-A1594V mutation showed nearly normal readings in all examinations. The members with both mutations displayed more severe LV hypertrophy and elevated LV filling pressure than those with 1 or no mutation (p < 0.05). Conclusion: Our results suggest that the pathogenesis of MYH7-V878A and CACNA1C-A1594V mutations may have a cumulative effect.

Percutaneous trans-apex intra-septal radiofrequency ablation of hypertrophic cardiomyopathy

Abstract A 70-year-old woman presented with severe hypertrophic obstructive cardiomyopathy (HOCM) (maximum ventricular septum thickness of 28 mm, peak pressure gradient (PG) in the left ventricular outflow tract (LVOT) of 153 mmHg). We performed percutaneous trans-apex intra-septal radiofrequency ablation (PTAISRA) of the interventricular septum under guidance of transthoracic echocardiography. At six-months follow up, the symptoms were significantly relieved; the septal thickness was reduced to 18 mm and the peak LVOT PG reduced to 44 mmHg. This case highlights a novel use of radiofrequency ablation for the treatment of HOCM. Long-term safety and efficacy merit evaluation.

Cardiomyocyte-targeted and 17β-estradiol-loaded acoustic nanoprobes as a theranostic platform for cardiac hypertrophy

BackgroundTheranostic perfluorocarbon nanoprobes have recently attracted attention due to their fascinating versatility in integrating diagnostics and therapeutics into a single system. Furthermore, although 17β-estradiol (E2) is a potential anti-hypertrophic drug, it has severe non-specific adverse effects in various organs. Therefore, we have developed cardiomyocyte-targeted theranostic nanoprobes to achieve concurrent targeted imaging and treatment of cardiac hypertrophy.ResultsWe had successfully synthesized E2-loaded, primary cardiomyocyte (PCM) specific peptide-conjugated nanoprobes with perfluorocarbon (PFP) as a core (PCM-E2/PFPs) and demonstrated their stability and homogeneity. In vitro and in vivo studies confirmed that when exposed to low-intensity focused ultrasound (LIFU), these versatile PCM-E2/PFPs can be used as an amplifiable imaging contrast agent. Furthermore, the significantly accelerated release of E2 enhanced the therapeutic efficacy of the drug and prevented systemic side effects. PCM-E2/PFPs + LIFU treatment also significantly increased cardiac targeting and circulation time. Further therapeutic evaluations showed that PCM-E2/PFPs + LIFU suppressed cardiac hypertrophy to a greater extent compared to other treatments, revealing high efficiency in cardiac-targeted delivery and effective cardioprotection.ConclusionOur novel theranostic nanoplatform could serve as a potential theranostic vector for cardiac diseases.

Echocardiography Guided Liwen Procedure™ for the treatment of obstructive hypertrophic cardiomyopathy in a patient with prior aortic valve replacement surgery: Liwen procedure for intra-myocardial radiofrequency ablation

We successfully treated a patient who was diagnosed of having hypertrophic obstructive cardiomyopathy after the aortic valve replacement surgery for the concomitant aortic stenosis. We report this first in kind new procedure exclusively developed in our center, Liwen procedureTM (percutaneous intramyocardial septal radiofrequency ablation), for patients with left ventricular outflow tract obstruction in spite of maximal medical therapy. The procedure was performed under transthoracic echo guidance. We discussed the technical details, safety, and effectiveness with corresponding images. The patient did well one year after the procedure without LVOT obstruction or arrhythmia.